The experience of adverse events is an etiological factor in the development of numerous mental disorders, yet some individuals are resilient in the face of adversity. An understanding of factors that promote resilience is critical to the development of more effective therapies. Human studies have suggested that coping factors are key, and that the actual or perceived ability to exert control over adverse events is an important coping process. The degree of behavioral control that an organism has over a stressor potently modulates the impact of the stressor, with uncontrollable stressors producing neurochemical and behavioral sequelae that do not occur if the stressor is controllable. Furthermore, an initial experience of controllable stress protects or immunizes against the typical negative outcomes of subsequent uncontrollable stress. The research to be conducted in this proposal will be directed at understanding the neural mechanisms that mediate the stress-buffering effects of coping/control. Prior work has identified a role for the medial prefrontal cortex (mPFC) as a structure that is sensitive to the dimension of control and here we will use genetic targeting strategies for monitoring and subsequently manipulating subcircuits embedded within the mPFC that are critical for immunization. Specific Aim I will determine if mPFC cells that are activated by an initial experience of control are also engaged during later adversity. Specific Aim II will determine if the mPFC is involved in mediating the effects of control because it participates in the corticostriatal action-outcome system, a circuit thought to be important for organisms to encode and use contingency information about the relationship between its actions and outcomes. The proposed research is the first of its kind, and will lay the groundwork for understanding how mPFC activity during coping behavior produces resilience to future challenge.